Endometriosis and adenomyosis are often regarded as variants of the same condition, i.e. dislocation of basal endometrium, but are distinct gynecological condition.
Adenomyosis, also known as endometriosis interna, is characterized by the presence of ectopic glandular tissue found in muscle. It usually refers to ectopic endometrial tissue (the inner lining of the uterus) within the myometrium (the thick, muscular layer of the uterus). The condition is typically found in women between the ages of 35 and 50. Patients with adenomyosis can have painful and/or profuse menses. However, because the endometrial glands are trapped in the myometrium, it is possible to have increased pain without increased bleeding. In adenomyosis, basal endometrium penetrates into hyperplastic myometrial fibers. Therefore, unlike functional layer, basal layer does not undergo typical cyclic changes with menstrual cycle.
Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus cavity, most frequently in the peritoneal cavity. Endometriosis almost exclusively affects pre-menopausal women and is a highly prevalent and highly underdiagnosed condition. There are an estimated 7 million endometriosis patients in the U.S., 12-14 million endometriosis patients in Europe and estimated 80 million in the rest of world. Endometriosis is a major cause of chronic pelvic pain, dyspareunia and sub-fertility. The condition is typically found in women between the ages of 15 and 50.
When analgesics like cyclo-oxygenase-2 inhibitors are not efficacious, treatments for endometriosis currently aim at reducing or suppressing menstruation and oestrogen production by the ovary. This is achieved by danazol, progestins, oral contraceptive pills or GnRH agonists. There are, however, many side effects, e.g. the use of GnRH agonists is limited to 6 months because of potential adverse effects on bone mineral density and treatment with danazol is also limited because of its androgenic side-effects. Moreover, in patients responding to treatment with GnRH agonists, symptom recurrence is reported in a majority of the patients within 5 years of treatment cessation.
The pain associated with endometriosis is the most difficult symptom to cope with for most women. For many, the pain they suffer severely interferes with every day life. It can be constant or it can be cyclical and coincide with a woman's period.
Recently, International Patent Application WO 2009/134718A1 (Repros Therapeutics) disclosed a method for treating an estrogen dependent condition comprising administering to a female in need thereof, a composition comprising an effective amount of a progesterone antagonist for an administration period beginning during the luteal phase of said female's menstrual cycle, wherein the endometrium of said female is not substantially thickened during said period. Endometriosis is listed as one of the numerous possible estrogen conditions.
This document also discloses a method for treating pain associated with, e.g. endometriosis wherein the progesterone antagonist is CDB4124 (Proellex®).
This document also shows the results of a 6 month study of Proellex® effect in the treatment of endometriosis. It is disclosed that “these results clearly support a dose response for CDB4124” and furthermore that “at the end of the first months of therapy, there was a statistically significant reduction in days of pain in the 50 mg Proellex group compared with baseline, but not in the three other treatment groups” (control group, Proellex 12.5 mg and Proellex 25 mg).
However, during Proellex'® clinical development program a dose related increase in liver enzyme (sign of liver toxicity i.e. Drug Induced Liver Injury [DILI]) has been observed when said drug was administered. (Press release published on Jul. 7, 2009 “Repros Therapeutics Inc. Provides Additional Information on Proellex Clinical Program”). As a consequence FDA decision was made to discontinue with Proellex® 12.5 mg, 25 mg and 50 mg (Press release dated Aug. 3, 2009 “Repros Therapeutics Inc. Suspends dosing of Proellex® and provides Update on Financial Status”).
For the moment no fully optimal treatment against pain associated with endometriosis or adenomyosis is currently available. The pharmaceutical products currently used namely non-steroidal anti-inflammatory drugs (NSAIDS) and hormonal treatments like danazol, progestins or GnRH agonists, alleviate pain symptoms in only less than half of the patients.
Thus, there remain significant unmet needs for efficient, safe and better long term therapies for treating pain associated with endometriosis or adenomyosis.